Functional chest pain of presumed esophageal origin is believed to be present in one-third of patients who undergo cardiac workup for angina pectoris. This condition induces significant clinical problems and reduces patients' quality of life and translates into a significant burden on healthcare resources. Comprehensive information on the central processing aspects of esophageal sensory physiology is critically needed for a better understanding of the mechanisms of esophageal functional disorders. This information will help improve the diagnosis and management of patients with noncardiac chest pain. Building on the findings of the last funding period, our specific objectives are: A. To investigate region-specific neural and neurocognitive cerebral cortical responses to esophageal viscerosensation in health and disease. We will 1) quantify, characterize and compare the neural and neurocognitive fMRI activity of the brain regions subserving the esophagus in response to mechanical and chemical sensory signals originating from the esophagus between healthy controls and patients with functional and organic esophageal disorders, 2) elucidate the age and gender differences in esophageal viscerosensation, 3) compare cortical activity induced by esophagus-related sensory and motor function, and 4) characterize and compare the effect of central sensitization on cortical response to esophageal stimulation between healthy individuals and patients with functional esophageal disorders. B. To characterize responses of the thoracic spinal dorsal horn (TSDHN) and nucleus tractus solitarius (NTSN) neurons to mechanical and acute and chronic chemical stimuli in a feline model. We will a) characterize the sensitization of TSDHN receiving projections from esophageal primary sensory afferents and NTS neurons receiving projections from the esophageal vagal afferent fibers by acid exposure, and b) elucidate the roles of glutamate (NMDA and AMPA) and neurokinin (NK1, NK2 and NK3) receptors in the development of their sensitization. We have assembled a multi-disciplinary, multi-departmental group of investigators to execute the studies proposed in this grant. The objective data obtained from healthy individuals and patients, as well as from our feline model are anticipated to significantly advance our understanding of the pathophysiology of esophageal sensory disorders and help improve diagnosis and treatment of this patient group.